FOCUS | CLINICAL

Hyperglycaemic
presentations in
type 2 diabetes

Clare Willix, Emma Griffiths, DIABETES MELLITUS refers to a group of young (MODY), late autoimmune
Sally Singleton metabolic diseases characterised by diabetes in adults (LADA) and gestational
hyperglycaemia, with end organ damage diabetes.2 For the purposes of this article
inflicted by the toxic effects of high plasma we will refer to the two main categories of
Background
Hyperosmolar hyperglycaemic state glucose. Symptoms of hyperglycaemia diabetes mellitus, T1DM and T2DM.
(HHS) is a syndrome that occurs in include thirst, polydipsia and polyuria. The prevalence of T2DM in Australia
patients with type 2 diabetes mellitus Patients with undiagnosed diabetes can has tripled over the past three decades,3
(T2DM) and is comparable to diabetic present with opportunistic infections such with an estimated one million Australian
ketoacidosis (DKA) seen in patients as thrush, and hyperglycaemia can lead to adults (5% of the population) living with
with type 1 diabetes. For a general
blurred vision due to lens oedema.1 T2DM in 2014–15.4 This prevalence is
practitioner working in a rural
emergency department, recognition
There are two broad pathophysiological based on self-reported diagnosis, and is
of HHS in a patient presenting with processes that lead to a diagnosis of likely an underestimate. The Australian
the triad of severe dehydration, diabetes mellitus.2 Type 1 diabetes Bureau of Statistics 2011–12 Australian
hyperglycaemia and hyperosmolality mellitus (T1DM) is caused by autoimmune Health Survey estimated that for every
is important to guide management destruction of pancreatic B cells and is four adults diagnosed with T2DM, there
and plan for disposition. defined by an absolute insulin deficiency.1 was one who was undiagnosed.5 Although
Objectives It usually becomes apparent in childhood the majority of T2DM diagnoses in
This article reviews the hyperglycaemic or teenage years, and survival depends on Australia are in people over the age of
states that can occur in patients with exogenous insulin replacement after each 55 years,3 there are increasing rates of
T2DM. The reasons for the biochemical carbohydrate-containing meal. young people (<25 years of age) being
derangements in both HHS and DKA Type 2 diabetes mellitus (T2DM) is diagnosed with T2DM, particularly in
are outlined, with a focus on the
associated with insulin resistance in target high-risk groups, including Aboriginal
recognition and management of HHS.
tissues and pancreatic compensation with and Torres Strait Islander peoples.6
Discussion high plasma insulin levels. It typically Some people living with poorly
Knowledge of the pathophysiology that occurs in mature-aged people. T2DM is controlled T2DM have a remarkable
influences HHS helps understand of
diagnosed when the pancreas is unable capacity for physiological compensation,
its clinical presentation and treatment.
to maintain sufficiently high levels of accommodating blood sugar
HHS has a high mortality rate (5–20%),
and having access to clinical guidelines insulin to allow for the peripheral uptake levels (BSL) >20 mmol/L without
from a referring hospital is useful to of glucose, resulting in hyperglycaemia. reporting symptoms. Hyperosmolar
guide early management strategies. This situation is referred to as a ‘relative’ hyperglycaemic state (HHS), however, is
insulin deficiency.1 a potentially life-threatening metabolic
Other rarer forms of diabetes mellitus derangement that occurs in T2DM as
include mature-onset diabetes in the a result of severe hyperglycaemia. This

© The Royal Australian College of General Practitioners 2019 REPRINTED FROM AJGP VOL. 48, NO. 5, MAY 2019 | 263
FOCUS | CLINICAL HYPERGLYCAEMIC PRESENTATIONS IN TYPE 2 DIABETES

syndrome was previously referred to as Hyperosmolar hyperglycaemic • hyperglycaemia (BSL >11 mmol)
HHNS or HONK, an abbreviation for syndrome (HHS) • venous pH <7.3 and/or bicarbonate
hyperglycemic hyperosmolar nonketotic HHS is the most likely diagnosis in the <15 mmol/L
state. It is rarer than diabetic ketoacidosis above case study. Risk factors for HHS • presence of ketones in the blood
(DKA), and is reported in <1% of hospital include newly diagnosed T2DM, being (>3 mmol/L).1
admissions for patients with diabetes,7–9 elderly, or having reduced ability for As with HHS there are guidelines for
but has a higher mortality rate of up oral fluid replacement.8 HHS is most management of DKA available from
to 20%, 10 times higher than that of commonly precipitated by infection, tertiary adult or paediatric referral
patients with DKA.9,7 This increase in but can also arise following myocardial centres.
mortality is attributable to the older age infarction, a cerebrovascular accident
and comorbidities (including an higher or pancreatitis.9
rate of venous thromboembolism) of HHS is characterised by 1) severe Differentiating between HHS
people diagnosed with HHS.8 hyperglycaemia (>30 mmol/L), which and DKA
leads to an osmotic diuresis. This Differentiating between HHS and DKA
leads to 2) profound dehydration, is important to guide management. The
CASE hypovolaemia and 3) plasma severe metabolic acidosis present in DKA
Brian, aged 61 years, presents to his hyperosmolality (>320 mosm/kg) with is the distinguishing feature. A comparison
local district hospital on a Saturday hypernatraemia.1,10 The hypernatraemia of the biochemical and epidemiological
afternoon accompanied by family can cause an altered mental state and, in features comparing the two syndromes is
members. He presents with severe extreme cases, coma.11 presented in Table 1. Clinically, Kussmaul
lethargy, weight loss (22 kg over the High insulin levels, a feature of the breathing is a characteristic feature of
past three weeks), polyuria and a insulin resistance found in T2DM, DKA, due to respiratory compensation for
sore mouth. His general practitioner supresses lipolysis and ketogenesis. metabolic acidosis; in HHS dehydration
(GP) had told him a month ago that Therefore, acidosis is not a defining is the most obvious clinical sign. For
his fasting blood sugars indicated he feature of HHS, although it can occur as both conditions the increase of counter-
was diabetic. Brian has not yet started part of an ‘overlap’ syndrome. A modified regulatory hormones (glucagon,
treatment but has been focusing on formula for calculating osmolality that can catecholamines, cortisol and growth
lifestyle factors. In a quest to lose be used at the bedside is shown in Box 1.10 hormone) fuel the ongoing metabolic
weight he took dietary advice from a The serum osmolality for the case study derangements.9 Fluid and potassium
friend and has persisted with a ‘fruit has been calculated as an example. replacement is a priority in both situations
only’ diet, eating only grapes over a but insulin therapy in HHS is delayed and
period of 72 hours. On examination he may cause vascular collapse if started too
appears severely dehydrated with oral Box 1. Modified formula for early (Figure 2).11
thrush, Glasgow Coma Scale 14 (eyes calculation of serum osmolality10 Patients with T2DM can develop
open to voice). His blood pressure is Plasma osmolality (mosm/kg) = 2(Na+) + ketoacidosis in some situations,
112/93 mmHg, heart rate 120 bpm, glucose (mmol/L) + urea (mmol/L) presumably due to B cell dysfunction as
temperature 37.8°C and respiratory = (2 × 148) + 48.2 + 27.4 a result of massive hyperglycaemia, and
rate 24. Bedside point of care testing = 371.6 mosm/kg some presentations of HHS may show a
includes venous blood gas (VBG) mixed picture. A euglycemic ketoacidosis
analysis: pH 7.38, lactate 4.4 mmol/L, can also result as a rare adverse effect
BSL >27.8 mmol/L (the upper limit of Comparison with diabetic of the sodium-glucose co-transporter 2
testing on VBG equipment), sodium ketoacidosis (DKA) inhibitors used to treat T2DM.1 In HHS,
(Na+) 148 mmol/L, potassium (K+) DKA, in comparison, is characterised by acute renal failure, precipitated by
5.1 mmol/L, haemoglobin (Hb) 171g/L an absolute insulin deficiency. Similar to hypovolaemia, can further exacerbate
and capillary ketones 1.0 mmol/L. HHS, hyperglycaemia causes an osmotic hyperglycaemia. Metformin should be
Subsequent pathology test results diuresis. In the absence of insulin, withheld in this situation due to the risk
include creatinine 175 µmol/L, urea glucose is unable to enter cells to allow for of lactic acidosis associated with the use
27.4 mmol/L and eGFR 35mL/min m2; normal energy production. This results of this drug.12
glycated haemoglobin (HbA1c) is in peripheral lipolysis, releasing free fatty
133 mmol/L (14.3%); BSL result acids (FFAs) as an alternative energy
from laboratory testing comes back at substrate for cell metabolism. These FFAs Management of HHS
48.2 mmol/L. Brian’s bedside troponin are then converted into ketoacids in the Most patients with HHS present with
is negative and his white cell count liver, resulting in a metabolic acidosis profound dehydration, hypovolaemic
is elevated. A chest X-ray shows a (Figure 1). The biochemical criteria for shock or, in severe cases, coma. Principles
right-sided pneumonia. diagnosing DKA include: of management follow.

264 | REPRINTED FROM AJGP VOL. 4 8, NO. 5, MAY 2019 © The Royal Australian College of General Practitioners 2019
HYPERGLYCAEMIC PRESENTATIONS IN TYPE 2 DIABETES FOCUS | CLINICAL

• Attention to the usual resuscitation

Hyperosmolar Diabetic priorities should be made: securing
hyperglycaemic Hyperglycaemia ketoacidosis a safe airway; ensuring adequate
state (HHS) (DKA)
ventilation; followed by correction
Relative       Decreased insulin       Absolute of fluid losses.
• Rehydration while maintaining
Free fatty
Amino
acids electrolyte homeostasis should be
acids the first focus of treatment. Normal
saline is used, with an aim to replace
Peripheral tissue Adipose tissue 3–6 L in the first 12 hours, and 50%
of the deficit in the first 24 hours.
Fluid replacement should take
into consideration comorbidities
Glycogenolysis and gluconeogenesis Ketone body production
such as cardiac and renal failure.
(betahydroxybutyrate and acetoacetate)
Rapid reduction in serum sodium
Hyperglycaemia should be avoided due to the risk of
Hyperketonaemia cerebral oedema and central pontine
Osmotic diuresis myelinolysis, hence normal saline is the
Acidaemia preferred rehydration fluid.10 Sodium
Profound dehydration levels may increase initially; this is
acceptable provided that osmolality
Figure 1. A comparison of the physiological changes in hyperosmolar hyperglycaemic state and is decreasing. The patient should be
diabetic ketoacidosis
encouraged to take oral fluids as soon
Reproduced with permission from Adam Rosh. as safe.11 Plasma osmolality should
be calculated hourly to ensure an
ECF ICF
appropriate response to therapy. An
example of an appropriate rehydration
schedule is shown in Table 2. The goals
A
of treatment are to gradually correct the
osmolality and electrolyte disturbances
to align with the gradual onset typical
of HHS.11
• As with DKA, total body potassium
B
H2O depletion is present in HHS despite
normal plasma levels.9 Potassium
should be added to the second bag of
Osmotic diuresis
intravenous (IV) fluids unless serum
levels are >5.5 mmol/L or urine output
C
is <0.5 mL/kg.
H2O • Hyperglycaemia: Rehydration
alone will help to reduce BSL, and
insulin infusion is only commenced
Osmotic diuresis
if ketonemia >1 mmol/L or if BSL
Insulin
reduction with IV fluids alone is
D
<5 mmol/L per hour.10 Figure 2 shows
Glucose the fluid shifts that occur in HHS,
and H2O and scenario D demonstrates how an
over-rapid correction of blood glucose
Figure 2. Fluid balance in hyperosmolar hyperglycaemic state 11 prior to rehydration can precipitate
a. Normoglycaemia and normal hydration; b. Early – extracellular fluid (ECF) is hyperosmolar, cardiovascular collapse.11 Blood glucose
causing water to shift from intracellular fluid (ICF) into ECF; c. Late – continued osmotic diuresis
levels should be kept at 10–15 mmol/L
causes dehydration, volume loss and hyperosmolality in both ICF and ECF; d. Insulin therapy
without adequate fluid replacement shifts glucose and water from ECF to ICF, causing vascular for the first 24 hours, and 10% glucose
collapse and hypotension. commenced if blood glucose falls
Reproduced with permission from UK Joint British Diabetes Societies for Inpatient Care (JBDS). too quickly. Following resuscitation
and return to normal fluid balance,

© The Royal Australian College of General Practitioners 2019 REPRINTED FROM AJGP VOL. 48, NO. 5, MAY 2019 | 265
FOCUS | CLINICAL HYPERGLYCAEMIC PRESENTATIONS IN TYPE 2 DIABETES

Table 1. Comparison of diabetic ketoacidosis and hyperosmolar hyperglycaemic state

Diabetic ketoacidosis Hyperosmolar hyperglycaemia state

Pathophysiology

Insulin Absolute deficiency Relative deficiency

Lipolysis/ketogenesis +++ +/–

Prodrome Shorter Longer

Patient factors

Age Younger Older

Diabetes type Usually type 1 Usually type 2

Biochemistry

Glucose >30 >30

Serum/urine ketones Present Absent

Venous blood gas:

pH <7.3 ≥7.3
Bicarbonate <15 mEq/L Normal or slightly decreased
Anion gap Elevated +++ Normal or slightly increased
K+ Normal or increased (despite total body deficit) Normal or increased (despite total body deficit)
Na+ Hypernatraemia uncommon Hypernatraemia common

Serum osmolality Variable Hyperosmolar

subcutaneous insulin should be

commenced.11 Table 2. An example of an appropriate fluid regimen10
• Treat any underlying disease process First bag 0.9% sodium chloride 1000 mL over 1 hour
such as infection which may have
Second bag Sodium chloride 1 L with 1000 mL over next 2 hours
contributed to the hyperglycaemic crisis.
40 mmol potassium chloride
• Venous thromboembolism risk: The
dehydration effects of HHS predispose Third bag Sodium chloride 1 L with 1000 mL over next 4 hours
40 mmol potassium chloride
patients to arterial and venous
thromboembolism, so anticoagulation Fourth bag Sodium chloride 1 L with 1000 mL over next 4 hours
with low molecular weight heparin is 40 mmol potassium chloride
recommended.10,11 Fifth bag Sodium chloride 1 L with 1000 mL over next 6 hours
• Foot care: Patients with HHS who are 40 mmol potassium chloride
obtunded or uncooperative are at high
Reproduced with permission from Fiona Stanley Hospital
risk for foot damage, so heel protection
and regular foot checks are important.10
• Disposition: Ensure expeditious
transfer of high-risk patients to a CASE CONTINUED HDU. After transfer to the medical ward
centre with a high dependency unit Brian has two large bore IV cannulae he receives education about diabetes
(HDU). Features of concern include inserted and IV fluids are commenced and is discharged home five days later
plasma osmolality >350 mosm/kg, according to local HHS guidelines.10 on twice-daily subcutaneous insulin.
signs of shock, reduced GCS, sodium He is encouraged to drink water as
>160 mmol/L or renal failure.10 We soon as feasible and is treated with IV
recommend adherence to the clinical antibiotics for a presumed community
guidelines of the referring hospital to acquired pneumonia. He was given a Key points
align treatment strategies, and that an 1 mg/kg dose of subcutaneous clexane • Patients with T2DM often present
early plan is made to transfer the patient and his heels are protected. Brian with non-specific symptoms,
to the nearest intensive care unit (ICU)/ was transferred by road to a regional but can rarely present as a
HDU facility. hospital and spends two days in the hyperglycaemic emergency.

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HYPERGLYCAEMIC PRESENTATIONS IN TYPE 2 DIABETES FOCUS | CLINICAL

• The triad of severe dehydration, Emma Griffiths MBBS, MPHTM, FRACGP, FARGP,
FAFPHM, Clinical Senior Lecturer, Rural Clinical
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